PROJECT SUMMARY/ABSTRACT An increasing number of children with medical complexity are exposed to polypharmacy in the ambulatory setting and take multiple high-risk medications daily. Polypharmacy can lead to serious adverse drug events (ADEs). The most vulnerable children with medical complexity exhibit a multitude of symptoms and have impairments that make the self-report of ADEs unfeasible, severely limiting the conduct of clinical trials and post-marketing drug surveillance studies to detect ADEs. Dr. James Feinstein?s overarching hypothesis is that repeated parent-reported symptom assessments (PRSA) before and after medication changes will provide clinically pertinent information, improve ADE signal detection, and enhance medication safety. This patient- oriented mentored career development award is designed to support the transition of James Feinstein, MD, MPH, an Assistant Professor of Pediatrics at the University of Colorado, into an independent clinician-scientist and to achieve his long-term career goal of becoming a national leader in pediatric polypharmacy and medication safety research. His short-term career goals are to (1) study factors involved in the escalation of polypharmacy and (2) implement a prospective PRSA system to guide and monitor pharmaceutical care for high-risk children. Dr. Feinstein will complete additional didactic and experiential training in 3 key areas necessary for his success: (1) pharmacoepidemiology and pharmacovigilance; (2) quantitative longitudinal data analysis; and (3) the design and conduct of prospective cohort studies. The University of Colorado Anschutz Medical Campus provides a unique research environment to conduct pediatric polypharmacy research, supported by collaborative research partnerships between the Adult and Child Consortium for Health Outcomes Research and Delivery Science (ACCORDS), The Skaggs School of Pharmacy and Pharmaceutical Sciences, and the Children?s Hospital Colorado Special Care Clinic for children with medical complexity. Dr. Feinstein?s renowned team of research mentors, Dr. Allison Kempe (health services research), Dr. Robert Valuck (pharmacoepidemiology), Dr. Chris Feudtner (children with complex chronic conditions), and Dr. Diane Fairclough (biostatistics), will guide completion of the proposed training and research plan. To achieve his short-term career goals, Dr. Feinstein proposes three research projects that will contribute to the implementation of a PRSA system to evaluate children with polypharmacy for medication- related issues. The specific aims are to conduct: (1) a retrospective cohort study to quantify annual polypharmacy and factors associated with escalation of polypharmacy; (2) a cross-sectional evaluation of symptoms in children with polypharmacy using PRSAs to advance our understanding of signal-to-noise and signal detection challenges; and (3) a prospective cohort study to assess whether using PRSAs prior to and after medication changes detects known ADEs. This innovative proposal could provide evidence to support the use of PRSA more broadly for the evaluation of other therapies in vulnerable children with medical complexity.